Universität zu Köln

Rattay, Stephanie ORCID: 0000-0002-9341-1911, Hufbauer, Martin ORCID: 0000-0003-4106-0520, Hagen, Christian, Putschli, Bastian, Coch, Christoph, Akguel, Baki and Hartmann, Gunther (2022). Human Beta Papillomavirus Type 8 E1 and E2 Proteins Suppress the Activation of the RIG-I-Like Receptor MDA5. Viruses-Basel, 14 (7). BASEL: MDPI. ISSN 1999-4915

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Abstract

Persistent infections of the skin with the human papillomavirus of genus beta (beta-HPV) in immunocompetent individuals are asymptomatic, but in immunosuppressed patients, beta-HPV infections exhibit much higher viral loads on the skin and are associated with an increased risk of skin cancer. Unlike with HPV16, a high-risk alpha-HPV, the impact of beta-HPV early genes on the innate immune sensing of viral nucleic acids has not been studied. Here, we used primary skin keratinocytes and U2OS cells expressing HPV8 or distinct HPV8 early genes and well-defined ligands of the nucleic-acid-sensing receptors RIG-I, MDA5, TLR3, and STING to analyze a potential functional interaction. We found that primary skin keratinocytes and U2OS cells expressed RIG-I, MDA5, TLR3, and STING, but not TLR7, TLR8, or TLR9. While HPV16-E6 downregulated the expression of RIG-I, MDA5, TLR3, and STING and, in conjunction with HPV16-E7, effectively suppressed type I IFN in response to MDA5 activation, the presence of HPV8 early genes showed little effect on the expression of these immune receptors, except for HPV8-E2, which was associated with an elevated expression of TLR3. Nevertheless, whole HPV8 genome expression, as well as the selective expression of HPV8-E1 or HPV8-E2, was found to suppress MDA5-induced type I IFN and the proinflammatory cytokine IL-6. Furthermore, RNA isolated from HPV8-E2 expressing primary human keratinocytes, but not control cells, stimulated a type I IFN response in peripheral blood mononuclear cells, indicating that the expression of HPV8-E2 in keratinocytes leads to the formation of stimulatory RNA ligands that require the active suppression of immune recognition. These results identify HPV8-E1 and HPV8-E2 as viral proteins that are responsible for the immune escape of beta-HPV from the innate recognition of viral nucleic acids, a mechanism that may be necessary for establishing persistent beta-HPV infections.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rattay, Stephanie UNSPECIFIED orcid.org/0000-0002-9341-1911 UNSPECIFIED Hufbauer, Martin UNSPECIFIED orcid.org/0000-0003-4106-0520 UNSPECIFIED Hagen, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Putschli, Bastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Coch, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Akguel, Baki UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Gunther UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-664640
DOI:	10.3390/v14071361
Journal or Publication Title:	Viruses-Basel
Volume:	14
Number:	7
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1999-4915
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYCLIC GMP-AMP; DOUBLE-STRANDED-RNA; INDUCIBLE GENE-I; RECOGNITION RECEPTOR; HUMAN KERATINOCYTES; E7 ONCOPROTEIN; ACID; HPV; 2ND-MESSENGER; INFECTION Multiple languages Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66464